Synthesis of novel 1,2-bis-quinolinyl-1,4-naphthoquinones: ERK2 inhibition, cytotoxicity and molecular docking studies

Abstract

Two novel series of N-2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones 3a-d and substituted N-(methyl/ethyl)bisquinolinone triethyl-ammonium salts 4e,f were successfully synthesized. The synthesized compounds were targeted as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. The synthesis involved the reactions of 2 equivalents of 4-hydroxy-2(1H)-quinolinones 1a-f and one equivalent of 1,4-naphthoquinone (2) in a mixture of ethanol/dimethylformamide (1:1) as a solvent and 0.5 mL EtN. In the reaction of 6-methyl-4-hydroxyquinolone 1b with 2, a side product 4b of the second series was obtained. In general, the presence of free NH-quinolone gave a single compound of the first series, whereas reaction of N-methyl/ethyl-quinolones 1e,f with 2 enhanced the formation of compounds of the second series. The structures of the new compounds were proved by different spectroscopic techniques such as IR, NMR (2D-NMR) and mass spectra, elemental analysis, and X-ray crystallography. To further elucidate the mechanism of action of these newly synthesized compounds, compounds 3a, 3b, 4e and 4f were selected to investigate for their MAP Kinases pathway inhibition together with molecular docking using ATP-binding site of ERK2. The results revealed that compounds 3a, 3b and 4f inhibited ETS-1 phosphorylation by ERK2 in a dose dependent manner. Also, compound 4f showed highest potency for ERK2 inhibition with ATP-competitive inhibition mechanism which was confirmed by the formation of three hydrogen bond in the molecular docking studies. The synthesized compounds were then tested for their in vitro anticancer activity against the NCI-60 panel of tumor cell lines. Interestingly, the selected compounds displayed from modest to strong cytotoxic activities. Compound 3b demonstrated broad spectrum anti-tumor activity against the nine tumor sub-panels tested, while compound 3d proved to be lethal to most of the cancer cell lines as shown by their promising GI and TGI values in NCI in vitro five dose testing. These results revealed that the synthesized compounds can potentially serve as leads for the development of novel chemotherapeutic agents and structure improvement will be necessary for some derivatives for enhancing their cellular activities and pharmacokinetic profile.

1,4-Naphthoquinones: Some Biological Properties and Application

“…Gene expression studies showed that p53, mouse double minute 2 homolog (Mdm-2) (a p53 regulator) and Bcl-2 (apoptosis inhibitor) were up-regulated during apoptosis induction by compound (61). 82) Two synthesized novel series of N-2,3-bis(6substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones and substituted N-(methyl/ethyl)bisquinolinone triethylammonium salts were described as new candidates to extracellular signal-regulated kinases 1/2 (ERK1/2) with considerable antineoplastic activity. These compounds inhibited ETS-1 phosphorylation by ERK2 and showed highest potency for ERK2 inhibition with ATPcompetitive inhibition mechanism.…”

Synthesis of New Fused Heterocyclic 2-Quinolones and 3-Alkanonyl-4-Hydroxy-2-Quinolones

“…We also synthesized fused naphthofuro[3,2- c ]quinoline-6,7,12-triones VI , and pyrano[3,2- c ]quinoline-6,7,8,13-tetraones, VII that have shown potential as ERK inhibitors [19]. Whereas syntheses of bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-naphthalene-1,4-diones VIII and substituted N -(alkyl)bis-quinolinone triethyl-ammonium salts VIV , were explored as candidates for extracellular signal-regulated kinases 1/2 (ERK1/2) having antineoplastic activity [20].…”

Synthesis of 3,3′-methylenebis(4-hydroxyquinolin-2(1H)-ones) of prospective anti-COVID-19 drugs

“…Quinolones show a significant similarity to some anticancer [ 4 ], anticonvulsant [ 5 – 7 ], anti-dermatities [ 8 ], antibacterial [ 9 ], antimicrobial [ 10 ], anti-Alzheimer [ 11 ] and pain relief [ 12 ] in addition to their medical, agricultural and industrial uses [ 13 – 15 ]. In previous work with quinolones, Aly et al, synthesized various classes of 2-quinolones such as 2′-amino-2,5′-dioxo-5′,6′-dihydro-spiro(indoline-3,4′-pyrano[3,2- c ]quinoline)-3′-carbonitriles [ 16 ], 3-(methyl-thio)-4-oxo-4,5-dihydrofuro[3,2-c]quinolone-2-carbonitriles [ 17 ], 3-(methylthio)-4-oxo-4,5-dihydro-furo[3,2- c ]quinolone-2-carboxamides [ 17 ], naphtho[2′,3′:4,5]furo[3,2-c]quinoline-6,7,12(5 H )-trione derivatives (as ERK inhibitors with efficacy in BRAF-mutant Melanoma) [ 18 ], 2,3-bis-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)succinates, arylmethylene-bis-3,3′-quinoline-2-ones [ 19 ], N -2,3-bis(6-substituted-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)naphthalene-1,4-diones and substituted N -(methyl/ethyl)bisquinolinone triethylammonium salts [ 20 ].…”